SE426835B - THERAPEUTIC PRODUCT CONSISTING OF A POLYMER WITH VINYL BENZENESULPHONATE UNITS - Google Patents

Description

10 15 20 7700670-8 2 R '___- C --- CH2--: (I) X SOBH wherein R is -H or -CH 3 and X is -H, alkyl or halo and in which any other units are units of one or more of the corresponding the amides and / or esters and / or units of the formula: -CH (R 1> c (R 2>) wherein B1 and H2 are the same or different and may be hydrogen or (C1-C6) alkyl, and RB may be acyloxy, aroyloxy, carboxy, carbamoyl, cyano (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxycarbonyl or aryl or of pharmaceutically acceptable non-toxic salts thereof, wherein the polymer has a viscosity average molecular weight of from 100,000 to 2,000,000 and contains less than 5% by weight of polymer with a viscosity average molecular weight of 20,000 or less.

In the case where the copolymer units are units of the formula: ïš in CH C (II) t I; 2 examples of groups R 1 and R 2 are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and pentyl, while R3 may mean acyloxy in the form of alkanoloxy having 1 to 18 carbon atoms, such as acetoxy, propionyloxy or butyryloxy, aroyloxy in the form of benzoyl oxy, (C1-C6) alkoxy in the form of methoxy and ethoxy, lower alkoxycarbon nyl in the form of methoxycarbonyl and ethoxycarbonyl or aryl in the form for example of mononuclear aryl, such as phenyl.

Preferred are "homopolymers" or alternatively block polymers. or random "copolymers" having a molecular weight of from 300,000 to about 1,000,000. Preferred vinylbenzene sulfonate units are units of the formula: --CH2 * -CH2-- // \\ SO3H 10 15 20 25 50 35 7700670-8 3 Preferred "copolymer" units are units of the formula: R2 IN R4 wherein R 2 represents hydrogen or (C 1 -C 6) alkyl and Ru represents acetoxy, carboxy, carbamoyl, lower alkoxy, lower alkoxycarbonyl or phenyl.

The "homopolymers" may be isotactic, syndiotactic or atactic.

As the term "molecular weight" is used herein refers to the average molecular weight of the viscosity. Too tight molecular weight distributions, the weight average molecular weight is close to the molecular weight.

Furthermore, in the present specification, the term "molecular weight distribution ratio "or" heterogeneity "ratio between the weight average molecular weight (fi w) of a polymer and this polymer number average molecular weight (One). For a unimodal polymer with only one molecular weight type is MW / Mn = 1.0. Higher numbers indicate wider or multi- pile distribution. The value for MW can be determined by light scattering or clay ultracentrifugation. Mn can be determined by osometry or measurement other coherent property such as the boiling point.

The MW / Mn ratio is most easily measured by gel permeation chromatography. which method was used for reported in the present description values.

Examples of specific monomers which can be used in poly- merisation with either sulfonated vinylbenzene or unsulfonated vinylbenzene are alkyl acrylates and alkyl methacrylates such as methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate, vinyl acrylate nitriles such as acrylonitrile, acrylic acid and methacrylic acid, ethylenically unsaturated anhydrides such as maleic anhydride, ethylenically unsaturated imides such as N-methylmaleimide, ethylenically unsaturated olefins such as ethylene, propylene and diisobutylene, vinyl esters such as vinyl acetate, vinyl propionate and vinyl benzoate and vinyl amides such as methacrylamide.

The products according to the invention have been found to give excellent control and regulation of wounds using common animal models.

Essentially complete control of gastric ulcer has been obtained at search with Shay rat and with a histamine-treated rat. Excellent control of duodenal ulcers has been obtained with histamine-treated guinea pigs as well as with steroid-treated rat. Continued dosing with from 10 15 25 STAY 'sn 7700670-8 u one-third to one-quarter of the healing dose when the wound has healed has proven effective and provided essentially complete protection against new uleus appearance.

The products according to the invention have also proved effective to inhibit the action of pepsin on proteolytic substrates, for to protect proteins from pepsin hydrolysis and to coat the mucosa to form a protective barrier against acid, pepsin, bacteria, fungi and other toxic substances.

The products according to the invention, in particular poly (sodium vinyl benzenesulfonate), has been found to possess specific binding to the lining of the stomach and duodenum. In these cases have the polymer was found to be retained in the stomach five to ten times longer than conventional non-retentive materials. It is believed that sulfone- the polymers of the present invention can be bonded to or adhere to intact and / or ground mucosal tissue to work such as a protective coating or barrier to prevent further re irritation or erosion as well as allow healing. It is assumed further that the material according to the invention can cooperate with secreted secretions to strengthen the mucosa mechanically and chemically and act as a protective barrier. Surprisingly, it has been found that certain polymers according to the invention also appears to function, at least in part, as an anti- secretory means even though they are non-systematic. treated guinea pigs treated with one of the polymers according to the finding, a marked reduction in secreted acid has been noted accompanied by increased mucus and obstruction of duodenal ulcers. As In comparison, the histamine-treated control animal was strong acid formation and severe duodenal ulceration.

Pharmacological studies using rats and dogs In histamine- as experimental animals indicate that the polymers and compositions containing these can be effective in stimulating formation and secretion of gastric and duodenal secretions to form one protective barrier on the mucous membrane. When the polymers according to the finding is administered in therapeutic doses in conventional carriers, have been found to promote wound healing, prevent damage to mucous membranes hinn fl yhan still anoint Lnvmuvnn, The polymers of the invention can also be used with others ulcerative conditions of the gastrointestinal tract such as reflux eso- fagit. 10 15 ß.) OUT 55 7700670-8 The products according to the invention have not unlike m fl íhtmrmdc carbohydrates or sulfated glycoproteins (Small example heparin) has been found to be an anticoagulant Unlike prior art sulfated and alkylsulfonated materials derived neither when dosed orally nor intravenously. from natural products, the aryl sulfonated products can be reproduced can be produced in clearly defined molecular fold ranges and shows hydrolytically stable polymer backbones as well as stable linkers coal to sulfur. The products according to the invention can be completely stable to acid or base hydrolysis and when present are such as sodium salt, they are thermally stable up to 20,000 comparison, it is mentioned that sulphated polysaccharides show varying degrees and broad molecular weight distribution, they are both hydrolytically unstable in terms of main chain and sulphate bonding as well as thermal bila.

The products of the present invention have not been Thus orally administered polymers of the invention have been found absorbed into circulating lymph or blood systems. be completely excreted in the stool. No absorbcrad polymer has been found in tissues or organs of treated animals.

In the literature it is reported that materials such as degraded gelatinous extract of carrageenan and sulfated amylopectin cause ulceration and haemorrhage in the cecum of guinea pigs or rabbits, when fed very high dosage levels. In contrast, it has been found that the compounds according to the invention do not show cecal ulceration in common guinea pig nor does it cause gastrointestinal irritation or toxicity in rats or dogs, when fed in such high doses as two grams per kilogram for 30 days or more.

U.S. Pat. No. 3,893,890 discloses sulfonated polystyrene polymers and copolymers with molecular weights in the range from Gow to 7 (100 (mo). they are given to guinea pigs or dogs, cause unpredictable These polymers and copolymers can, when logical reactions including extreme irritation and toxicity (see Table II in this description). It has been observed that toxic and irritation are inversely related to the molecular weight and by careful choice of molecular weight and molecular weight ratio. division, for example by removing low molecular weight materials cooling weight, therapeutic safety can be achieved. This discovery is completely unexpected, because, as noted above, degraded gelatinously 10 15 20 25 30 55 77 00670-8 6 _ Carrageenan extract (molecular weight about 30,000) and sulphated æm fl opäd äd n (molecular weight about 60 X 10) are reported to be ulceragenic when given to ordinary guinea pigs in concentrations from 1 to 3 g / kg (see for example R. Marcus and J. Watt, Gastroenterology 67, U73, l97H and P. Grasso et al., Fd. Cosmet. Toxicol ll, 555, 1973). Even polymers and copolymers having viscosity average molecular weights of about 500,000 to about 600,000 or more can show significant degrees of toxicities at doses of 1 g / kg and day when the polymers have such a wide molecular weight cooling weight distribution that they contain undesirable levels of more low molecular weight.

This discovery that the toxicity is due to the presence of poly- more with molecular weights up to 50,000 form a basis for choice of the preferred class of polymers for the products according to the finding. , As for the molecular weight distribution, it is obvious that of course The lower the molecular weight, the lower the molecular weight distribution should be be, then otherwise an undesirably large amount of material with low molecular weight will be present. As management has been noted that polymers with an average molecular weight of from 100,000 to 2,000,000 should have a narrow molecular weight distribution (ie One / fi% = 1.05 - 1.30) at the lower viscosity average molecular weight, but may exhibit a broader molecular weight distribution (ie fi w / Én = 1.3 - 8) at it higher average molecular weight. This can be accomplished by selectively removal of low molecular weight fractions, for example by fractional precipitation extraction, ultrafiltration or gel permeation by intentional use of polymerization conditions and processes which, if necessary, reduce the formation of low molecular weight materials to a minimum. Such techniques are known in the art and varies with the particular polymer, which to be produced.

Compositions containing the polymers of the invention as active ingredient and also the polymers themselves are active anti-ulcer agents, which can be administered in a wide variety of peutotic doses in conventional carriers. The products can be administered in many different pharmaceutically acceptable carriers, for example in a flavored aqueous solution divided into a plurality, usually three or four, doses per day. Standard preparations contain from about 10 to 25% of the product in a suitably flavored, colored, thickened, preserved and water-based mixture. The liquid 10 15 20 25 50 55 7700670-8 the dosage form may contain, in addition to water, small amounts of ethanol or other pharmaceutically acceptable solvent, or available solvents. Other dosage forms include gels prepare with pectin, agar, hydroxyethylcellulose or other approved gelling agents, tablets, capsules, pills, which may be micro- encapsulated or coated for prolonged action.

In addition, the preparations may contain combinations of agents particularly suitable for healing wounds and for relieving pain, such as antacids, anti-cholinergics and the like.

Other drugs may also be included in the compositions of the invention.

It is the intention that an adult patient with average body weight (70 kg) should be given a dose of 2 to 10 g of polymer according to the invention per day in acute illness and 0.5 to 2 g of it Thus unit dosage forms for adults may contain from 0.1 to 2 g or In any case preferably, the unit dosage forms should be as appropriate as possible polymer in chronic disease (or as a preventive dose). even more of the polymer per unit dose. covers a dose range of 10 mg to about 500 mg / kg body weight and day and in particular 10 mg to 200 mg / kg body weight and day, and in particular, the range is between about 20 mg and 150 mg / kg of body weight. weight and day. The product can be administered in divided doses in in the form of scored tablets or capsules, however, liquid dosage forms are preferred. These dosage forms allow symptomatically dose regulation for the patient to be treated.

The following examples illustrate the preparation of various compositions. ions containing the active ingredients of the invention. 10 15 20 25 77006 70-8 Example A - Tablets containing 500 mg of active ingredient per tablet Per tablet Poly ((sodium vinylbenzenesulfonate) M = H00 000, - ñw / Mn = 1.1 500 mg Diabasic calcium phosphate 73 mg Lactose 70 mg Corn starch 50 mg Magnesium stearate 7 mg 700 mg Each component is weighed and passed through a sieve with a mask. vidd H0 mesh (U.S. Sieve). The ingredients are mixed in a mixer with double jacket for l0 minutes and compressed to form tablets weighing 700 mg per tablet on a tablet machine.

Example B - Oral elixir dosage form containing 500 mg of active ingredient ingredient per five ml Per 5 ml Poly (sodium yinylbenzenesulfonate) 1 M = H00 000; MW / Mn = 1.1 750 mg Sorbitol solution 70% w / w 1000 mg Ethyl alcohol 500 mg Propylparaben 5 mg FD & C yellow No. 5 0.2 mg Flavor 0.03 mg Purified water q.s.

Poly (sodium vinylbenzenesulfonate) is dissolved in part of the water by gentle stirring. The sorbitol is added to this solution.

FD & C yellow no. 5 is dissolved in a part of the water and added to the above ethyl ethyl alcohol. Taste- The diethanol solution. Propyl paraben is dissolved in a part of the additive is dissolved in residual ethyl alcohol. the solutions are then added to the above aqueous solution.

Then a sufficient amount is added with continuous stirring water To achieve final volume. l0 15 20 25 50 55 77006 70-8 Example C - Oral solution containing 500 mg of active ingredient part per five ml Per 5 ml Poly (sodium ylbenzenesulfonate) M = 800,000; MW / Mn <í1,1 750 mg Propylene glycol 100 mg Saccharin sodium 0.05 mg Propylparaben 5 mg Flavor 0.03 mg FD & C yellow No. 5 0.2 mg Purified water q.s.

Poly (sodium vinylbenzenesulfonate) is dissolved in a quantity of water with gentle stirring. Saccharin sodium is dissolved in a small amount of water.

FD% & C yellow no. 5 is dissolved in a small amount of water. These two solutions is added to the polymer solution. Propyl paraben is dissolved in a small part of propylene glycol, and the flavoring is dissolved in the remaining amount propylene glycol. The two propylene glycol solutions are then added to the above aqueous solution. Sufficient amount of water is then added to bring to the final volume for continuous stirring. Sample U - Dry capsules containing 250 mg of active ingredient part per capsule Per capsule Poly (sodium ginylbenzenesen sulfonate M = 220,000; MW / Mn = 1.1 250 mg Magnesium stearate 2.5 mg 252.5 ms The poly (sodium vinylbenzenesulfonate) and magnesium stearate are weighed and passed through a HO mesh screen. Ask- the constituents are now mixed in a double-jacketed mixer for 10 minutes.

Gelatin capsules No. 0 are filled with 252.5 mg of mixed product.

The polymers according to the invention can be prepared according to one of two ways, either by sulfonating a polymer containing the vinylbenzene units or by polymerization of a salt, an ester or amide of vinylbenzenesulfonic acid. According to the sulfonation the process, the polymer is treated with a sulfonating agent, to for example sulfur trioxide, in the presence of a complexing agent, to for example an ether such as dichloroethyl ether or dioxane, an amine such as pyridine, an amide such as dimethylformamide, an ester such as triethylformamide phosphate, or sulfuric acid at a temperature of from -5000 to 5000 for 1/2 to 12 hours. 10 15 50 35 HO 7700670-8 10 According to a preferred sulfonation method a solution of linear polystyrene in ethylene dichloride at a temperature of OOC or lower with a complex formed of sulfur trioxide (1 mol) and dichloroethyl ether (2 moles). neutralized with a base such as sodium hydroxide, potassium hydroxide or Any excess salt is then removed from The reaction mixture sodium bicarbonate. the aqueous solution, for example by dialysis to provide a substantially pure and aqueous solution of sulfur fused polyvinylbenzene, which is released after water removal gives a substantially pure product.

Alternatively, the sulfonated product can be filtered or centrifuged from the reaction mixture. Any surplus of sulfonation complexes can be removed by washing with solvent, for example diethyl ether. The product is then usually dissolved in water and neutralized. The partially or completely neutralized product can also be isolated in solid form, for example by freeze-drying, vacuum drying or spray drying. When the solid product is partial neutralized, it can be added with sufficient base amount to achieve complete neutralization upon dissolution. Suitable bases include carbonates or bicarbonates of the alkali metals, especially sodium or potassium. The filtration procedure before neutralization is preferred by removing some low molecular weight compounds.

The degree of molar sulfonation of the phenyl ring can be controlled by varying the molar ratio of the sulfonation agent used medlet. aromatic mers exhibit formula I above.

A second process for preparing poly (vinylbenzenesulfonic acid) Preferred polymers are those in which at least 90% of the present the ants) include polymerization or copolymerization of vinylbenzenesulfonic acid salts by solution polymerization in water or organic solvents such as alcohols, tertiary glycols amines, amides and mixtures thereof using free radicals radical catalysts including ammonium persulfates, peroxides and hydrogen peroxides. Redox systems can also be used as well as ultra- violet radiation. The monomer solutions can be in the range from 10 to 50% by weight. v Vinylbenzene polymers suitable for sulfonation can be prepared by means of cationic catalysts such as sulfuric acid or fluoride complexes, free radical catalysts such as benzoyl peroxide, ammonium persulfate, azobisiobutyronitrile, hydrogen peroxide, tert-butylhydrogen peroxide or with anionic initiators. The free radical polymers can 10 15 20 25 35 H0 77 006 70- 8 ll prepared with free radical catalysts in solution, dispersion, emulsion, or in bulk by methods well known to those skilled in the art, A preferred polymerization process is anionic polymerization. vinylbenzene or substituted vinylbenzene monomer.

This process can directly yield polymers with a ratio weight average weight (mw) to time weight weight (mn) 1 to 1.5. The polymer molecular weight is controlled by the amount in the monomer present in the initiator mixture and in initiator, i.e. of from reactive molecular weight is a function of the number of grams of monomer divided by the number of moles of initiator. Useful initiators include lower alkyl lithiums, such as n-butyllithium, sodium alkyls, sodium aryls such as sodium naphthalene and lithium aryls such as phenyllithium, acrylate ethyls such as sodium benzophenone and finely divided sodium. Loose- agents in which the reaction may proceed include benzene, toluene, aliphatic ethers such as diethyl ether, alicyclic ethers such as dioxane along with aliphatic hydrocarbons such as heptane. _ A preferred class of polymers are homopolymers of vinyl benzene, polymerized down an anionic initiator to a MW / Mn less than 1.5 in the molecular weight range l00 000 to l 000 000 and sulfonated with complex sulfur trioxide to a higher sulfonate degree of degradation of the benzene ring than 90%.

Anionic polymerization is preferably carried out in the absence of Reactive Chain Ending Formxnámgnn This technology offers usually polymers down a ratio WW / Üg lower than 1.3.

The reaction can be carried out in an inert atmosphere such as dry argon or dry nitrogen gas. Both solvents and monomers to be used, is usually dried, freed from oxygen and titrated with an adduct of catalyst and monomer to remove impurities. The an- the ionic polymerization is usually carried out at a temperature in range from about 0 to BOOC.

The polyvinylbenzenes can also be prepared by using free radical catalysts of standard type, such as those specified above, under such conditions that only partial conversion happens. (30 to 80%) of monomer to polymer By regulating catalyst to monomer ratio and controls the conversion street, a value for the ratio Ü; / Mk, which approaches 1.5 achieved. This procedure is described by J.H. Duerksen and A.E.

Hamieiec, J. P61y.sc. Part o, No. 25, 155-166 (1968) and L.H. Peebies, Mol.Wt. Dist. in Polymers, Interscience (1971) whose content The polymer can be isolated by hereby incorporated into the present text. 10 15 20 25 50 35 Ä0 7700670-8 l2 standard methods but is preferably isolated by de-volatilization in a screw extruder to provide substantially monomeric free polymer groats.

The polyvinylbenzenes useful in the invention can can also be prepared by means of ordinary solution, mass or emulsion free radical technology. IN molecular weight distribution for example from about * 2 to about 8.Genmnvalav In these areas, polymers with wider ones are obtained a high average molecular weight polyvinylbenzene, for example around l x 10, the broad molecular weight distribution can be from about 2 to 8 be used to provide therapeutically safe polyvinylbenzenesulfonate nater. At an average molecular weight of about 250,000, the molecular weight is required. distributions of from about 2.5 to about 30 to ensure that a therapeutically safe polyvinylbenzenesulfonate is obtained.

Anionic copolymerization can usually only yield "segments" - polymer when a ratio MW / fi ñ lower than 1.3 is required. Two monomers are copolymerized by anionic mechanism, wherein a monomer reacts with the polymer anion of the other monomer, to examples of copolymerization of styrene and methyl methacrylate, a initiator such as n-butyllithium is used and the styrene is polymerized to the desired molecular weight. Methyl methacrylate is then added to the meranions and polymerized at the end of each polystyrene chain for the formation of block polymers. Mobomers suitable for breathing in anionic copolymerization are those which polymerize through anionic mechanical and does not have functional groups such as kaboxi, hydroxy and the like, which destroy an anion. Post-sulfo produces a copolymer containing segments of polyvinyl benzenesulfonate and poly (methyl methacrylate). W_m When copolymers are prepared with free radical catalysts, the limitation in terms of types of useful comonomers is smaller strictly than in anionic polymerization. Any monomer like resists post-sulfonation, can be used including acrylates, methacrylates, vinyl nitriles, vinyl carboxylic acids, olefins, vinyl esters and other monomers included in formula II above.

The second process for the manufacture of products (I) according to the invention mentioned above comprises polymerization or copolymerization. lymerization of salts, esters or amides of vinylbenzenesulfonic acid and associated derivatives. Specific examples of useful harmonics more include acrylates, methacrylates, vinyl nitriles, vinyl acids such as methacrylic and acrylic acid, crotonates, clefins, anhydrides, nyl esters, vün fl et fi ng vüwlüü fi er, vinyl halides, vinylamides, vi- nyl ketones as well as other common vinyl and vinylidene monomers. 10 15 20 25 30 35 HO 77006 70-8 l5 Preferred monomers are methyl methacrylate, methacrylic acid, acrylic acid, methacrylamide, maleic anhydride, acrylonitrile, N-methyl-maleimide as well as styrene. Usually the content of sulfone monomer is at least 50% monomer units and preferably higher than 60%.

Molecular weight is a limiting parameter in terms of viscosity. the density of the polymeric drug solutions and in order to avoid the madness of the reaction mixture during sulfonation. Thus is one practical upper molecular weight limit for an unsulfonated polymer or copolymer 1,000,000.

Non-toxic pharmacologically within the scope of the invention acceptable salts of the polymers. In general, any base, which forms salt with the acids and whose cation possesses pharmaceutical ecological properties, which do not cause adverse physiological effects in the incorporation of the body system, within the scope of the invention and Thus, cations include, for example, alkali metal cations and alkaline earth metals, zinc, aluminum, iron and lampshades the cations of ammonia, primary, secondary and tertiary amines such as mono-lower alkylamines such as t-butylamine, di-lower alkylamines such as diisopropylamine, tri-lower alkylamines such as triethylamine, nitrogen-containing heterocyclic amines such as piperidine and alkanolamines such as triethanolamine. Within the scope of the invention are also ester and amide derivatives of the sulfonic acids (I) prepared according to conventional procedures well known to those skilled in the art and to such an extent that these derivatives are both non-toxic and physiologically acceptable body system and represents a smaller (less than 50%) of the total product monomer units and are considered to be functional equivalent to the sulfonic acids and their salts.

Poly (vinylbenzenesulfonic acid) (acids) have a greater tendency to decomposed by actinic light or heat than the corresponding salt and should not be heated to a temperature higher than 100 ° C and should be stored in light-protected containers or is suitably stabilized by chemical methods.

The following example illustrates the preparation of some products according to the invention.

Example 1 - Poly (vinylbenzene) Step A - Titration of n-butyllithium A solution of n-butyllithium in hexane (2, HM, 2 ml) sat and dropwise to a mixture of diethyl ether (5 ml) and distilled water (5 ml) in an Erlenmeyer flask. When the additive is complete, wash the piston walls with distilled water and a drop of 1% 10 15 20 25 STAY 55 H0 7700670-8 leeward (weight) bromophenol blue solution is added. The solution is titrated with hydrochloric acid (0.100N) until the blue color disappears.

/ The total base content of the initiator is determined as follows method: ml of 0.1ON HCl (normality of H01) = molar base based on 2 ml n-butyllithium /. Bases other than n-butyllithium are determined by adding a solution of n-butyllithium in hexane (2 ml) to pure and dry 'allylbrnmide under a nitrogen atmosphere. Distilled water is then added together with a drop of 1% bromophenol blue. Titration of this mixture with hydrochloric acid gives concentrated of the remaining base, according to the above equation.

This gives the number of millimoles of other present bases.

Since the solution "2, ÄM" gives a total base content of 2.63M and a residual base content of 0.55M is the true content of n-butyllithium 2, U8M, i.e. (2.63-0.15).

Step B - ~ Anionic polymerization of vinylbenzene Benzene (1200 ml) in a dry and round bottom, with three necks fitted piston volume 2 liters and equipped with a three-way shut-off valve, reflux condenser, magnetic stir bar and torque is brought to 6000 under argon. Ä0 ml of benzene is transferred to a dry 100 ml flask under argon, then vinylbenzene (0.1 ml, 0.36 g, 5.5 mmol) and n-butyllithium in hexane (0.5 mL of 2.0 M) solution, 1.2H mmol) is added. This initiator mixture is kept at room temperature for about 15 minutes, during which time period it the bright orange color of the vinylbenzene and n-butyllithium adduct becomes visible. This initiator solution is added to the hot benzene (1 160 ml) until a light yellow color remains in the warm reaction environment for at least 30 minutes to remove contaminants.

An amount of 00 ml of purified benzene is added to a second dry flask with a volume of 100 ml under argon and a second initiator solution is prepared as above. This gives a solution of 0.03 lM in initiator. Bone- the tendon (120 ml) is cooled to 1000 and vinylbenzene (110 ml, 100 g) is added. at 1000 until a faint yellow color persists for 30 minutes.

The resulting solution is heated to 3000 and 16 ml of the above This solution is titrated with a freshly prepared initiator solution. 0.03lM initiator solution (0.5 mmol initiator) is added rapidly in a portion while stirring vigorously. Within 10 minutes, one develops 3000 exothermic reaction. Within 20 minutes, the reaction mixture is very viscous. The thermal reaction subsides after 1 hour.

The resulting viscous and orange solution is kept at 5000 in 1.5 hours, and then cooled to ambient temperature. Approximately 1 ml of isopropanol is added to quench the reaction. The 10 15 20 25 STAY (J) U'ï HO 77006 70 ~ 8 15 the resulting colorless solution is transferred to a separatory funnel and slowly and dropwise to three liters of isopropanol under stirring. Good shear effect is necessary here to give a finely divided sample. The white polyvinylbenzene collects through The remaining isopropanol is removed in vacuo Analysis by gel titration. to give 100 g of polyvinylbenzene (yield 100%). permeation chromatography shows a value for Üw / Én equal to 1.13 and a molecular weight of 221,000.

By mainly following the procedure described in the example 1 above and using 100 g of vinylbenzene and 2.3, 0.28 and 0.13 mmol n-butyllithium, polyvinylbenzenes having a molecular weight of 49 ooo, 1150 ooo and 970 ooo, respectively, eemtilw / ían ev 1.17, 1.08 respectively 1.05.

Example 2 - Poly (sodium vinylbenzenesulfonate) (M = 6,0002) 100 g peiyvinyibeneen mean = 321 ooo a law / Mn = 3.8 (Aidrien Chemical Co) is sulfonated by mainly following the procedure of Example 5 to give a polymer with a predicted molecular weight of about 6H2,000 and predicted value Üw / Mn = 3.8.

The polymer was ultrafiltered through an 80,000 cut unit hollow fibers.

Example 6 - Poly (sodium vinylhene sulfonate) Sulfur trioxide (115.3 g, 1.1 MH moles) is added to a cooled (-1000) solution of ethylene dichloride (5 liters) and dichloroethyl ether (H11 g, 2.88 moles). 0.9 mol) with a viscosity average molecular weight of 200,000 and Üw / Mg = 1.1 in anhydrous ethylene dichloride (1000 ml) is then added slowly, wherein the additive tube is kept above the surface and the temperature is maintained between -1000 and -500. After complete addition of polystyrene solution, allow the reaction mixture to warm to 1500 ° C and kept at this temperature for four hours. Deionized water (000 ml) is added and the reaction mixture is stirred for 15 minutes.

Aqueous sodium hydroxide (50%) is added to a pH of 7-10 and may The organic layer A solution of filtered polyvinylbenzene (100 g, stirring is continued for 50 minutes. The reaction mixture undergo phase separation for about 12 hours. removed, and residual layers of water and poly (vinylbenzene) sulfonate salt is heated to 5000 under a partial vacuum of about BUU mm Hg to remove any remaining organic solution ningsmudel. The reaction mixture is then diluted with an equal volume first deionized water (prouenthalten solid particles at this point is approximately 2, ü%). Sodium sulfate is removed by ultra- filtration, whereby the effluent stream is recycled to 10 20 25 30 35 H0 7700670-8 16 Fresh deionized water is added to the supply The permeate is collected the supply tank. the idea of maintaining a constant pressure. in a separate receiver and is periodically examined with respect to polymer content using a content of a quaternary salt and an inorganic salt by conductivity measurements. For it if a precipitate is observed, the dialysis must be stopped and the membrane Ultrafiltration is stopped when the resistance of the permeate is measured Once the salt has been removed, exchange a conductivity bridge at 8-10,000 ohms / cm. concentrate the remaining solution to give a yield 90f95% of poly (sodium vinylbenzenesulfonate) with a viscosity agent molecular weight of about 1400,000 and MW / Mn lower than 1.2.

Example U - Copolymer of sodium vinylbenzenesulfonate and methacrylic acid (M = 615 000) (2: 1) A solution of deionized water (50 ml) (0.66 g, 0.009 mol, 50%) in a 500 ml round bottom flask and equipped with three necks and mechanical stirrer, thermometer, drip funnel and reflux condenser are heated to 6000 over a period in 10 minutes. A second solution of sodium vinylbenzenesulfonate (61, 8 g, 0.296 mol) and methacrylic acid (1.2.9 g, 0.1H98 mol) in water (225 ml) at 0 ° C is added to the reaction flask over a period of 17 minutes. The resulting solution is stirred over water (20 hours) at 6000. Then the solution is cooled to room temperature and neutralized to pH 7.7 by the addition of a sodium hydroxide solution (10.0 g, 0.125 mol, 50%). The neutralized solution dialyzed for M8 minutes against running deionized water, concentrated and hydrogen peroxide and lyophilized to give 60 g of copolymer in the form of a light brown solid product (M = 615,000, MW / fi nš2, É) by means of gel permeation matography Example 5 - Copolymer of vinyl benzenesulfonate and methacrylic acid (M = B50 o> oo) (2,117 = 1) The following solution is prepared in a flask and allowed to stand, under one nitrogen blanket, at room temperature for 13 days: Sodium vinylbenzenesulfonate (duPont) 9l% ..... . . . . . 61.8 g, (0.27 Å mol) Methacrylic acid ................ l2.9 g, (0.5 mol) Water ...................... 260 ml Ammonium persulfate .......... 0.5 g (0.0022 mol) The solution is neutralized to pH 7.5 by adding sodium hydroxide solution (19.5 g, 0.28 mol) and dialyzed against running deionized water for 2ü hours. The dialyzed solution was centered and lyophilized to give 27.8 g of the copolymer 10 15 20 30 UO 77006 70-8 I 17 such as a white solid product (M = 850,000). MW / in = 2.55 by gel permeation chromatography.

Example 6 - Copolymer of sodium vinylbenzene sulfonate and methacrylic âíïâ M = 628 100 (2.2: 1) Nitrogen gas is bubbled through a solution of sodium vinylbenzene sulfur phonate (61, 8 g, 0.2 μmol, 91.5%) and methacrylic acid (1.2.9 g, 0.98 mol) in deionized water (255 ml) in a round bottom flask with a volume of 500 ml and equipped with three necks, mechanical stirrer, thermometer, reflux condenser and nitrogen bubbler for 1 hour time in order to vent the solution. The solution, under nitrogen, is heated to 5000 and hydrogen peroxide (1.3 g, 0.135 mol, 55%) is added.

This polymerization mixture is stirred at 5000 under nitrogen for 20 h hours, cooled and neutralized to pH 7.5 by adding 50% aqueous sodium hydroxide (1.2 g, 0.125 mol). The neutralized solution is dialyzed for H8 hours in running deionized water, concentrated to 600 ml and lyophilized for EH hours to give 62. H g copolymer (M = 628,100).

By essentially following the procedure of Example 6 copolymers are obtained with the following ratio and molecular weight: a. svBs (2) / MAA (1) M = 915 100 b. svBs (2) / MAA (1) M = 686 1150; fi w / line = 2.8 Example 7 - Poly) (ammonium vinylbenzenesulfonate) A solution of poly (sodium vinylbenzenesulfonate) is passed through a column of AMBERLITE IRJQO in H + form, to convert the polymer sodium salt to the free acid. The solution is titrated to determine meq of H + / ml. This solution is then stirred with a equimolar amount of a 29.8% ammonium hydroxide solution for one hour.

The solution is lyophilized to give poly (ammonium vinylbenzene). sulfonate). 7 I Example 8 - Glycine salt of poly (vinylbenzenesulfonic acid) A solution of poly (vinylbenzenesulfonic acid) is stirred with glycine for one hour, concentrated and lyophilized to give glycine the salt of poly (vinylbenzenesulfonic acid).

Example 9 - Calcium salt of poly (vinylbenzenesulfonic acid) A solution of poly (sodium vinylbenzenesulfonate) in water passed through a column ai AMBERLITE2 IR 120, Ca ++ ~ fOrm, to replace Na + with Ca ++. The effluent from this column is concentrated as well lyophilized to give the calcium salt of poly (vinylbenzenesulfonic acid).

Example 10 - Magnesium salt of poly (vinylbenzenesulfonic acid) A dialyzed solution of poly (vinylbenzenesulfonic acid) from 10 1 É » 20 25 NO 77 006 70- 8 18 Example 7 (150 meq) is stirred over water with magnesium carbonate (7.3 g, 129.2 meq Mg ++). This solution is filtered to remove any solid undissolved particles and then dialyzed for H8 hours.

The resulting solution is concentrated and lyophilized to give the magnesium salt of poly (vinylbenzenesulfonic acid).

Example 11 - Copolymer of sodium vinylbenzene sulfonate and ethyl methacrylate (2.5: 1) Step A - Copolymer of vinylbenzene and ethyl methacrylate A solution of vinylbenzene (78 g, 0.75 mol), ethyl methacrylate (5U, 2 g, 0.50 mol), benzoyl peroxide (3.0 g, 0.011 mol) and toluene (70 ml) in a 1 liter round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and addition funnel, heated to reflux (11H ° C). vinylbenzene (26 g, 0.25 mol), ethyl methacrylate (11 μg, 0.10 mol) and benzoyl peroxide (1.0 g, 0.00H mol) in toluene (H00 ml) are sieved via the addition funnel over a period of four hours. The effluent The solution is then evaporated A second solution containing continues for another two hours. to dryness and the glassy residue is dissolved in acetone (500 ml).

The polymer is isolated by pouring the acetone solution into methanol (5,000 ml) with stirring. The copolymer is collected and dried over overnight in a vacuum oven at HOOC to give 110.0 g (yield 100%) : u-zlupo l ym rer.

Step B - Copolymer of sodium vinylbenzene sulfonate and Ethyl acrylate fill a solution of sulfur trioxide (sulfan B) (μl, 5 g, 0.52 mol) in symmetrical dichloroethyl ether (lüš g, 1.0 mol) and ethylene dichloride (700 ml) at -1ü ° C in a two liter round bottom flask equipped with thermometer, mechanical stirrer and addition funnel a solution of I a copolymer of vinylbenzene and ethyl methacrylate (53 g) in ethylene chloride (350 ml) at ~ 15 ° C over a period of 12 minutes. The cooling bath is then removed and the reaction mixture is allowed to stand A cut solid product Any room temperature over a period of three hours. Separate by filtration and dissolve in water (600 ml). residual organic solvents are removed and the solution neutralized to pH 7.8 by the addition of sodium hydroxide solution (50 g, 0.625 mol, 50%). lysed for H8 hours, concentrated and lyophilized to give The neutralized solution was 80.5 g of nampolymer with a molecular weight of 750,000.

Example 12 - Copolymer of sodium vinylbenzene sulfonate and meth. acrylic acid (1.0: 1.2) A solution of water (50 ml) and ammonium persulphate (2.0 g, M7 10 15 20 f n LI | CH 40 7700670-8 19 0.087 mol) in a round bottom flask with three necks and volume 500 ml and equipped with a mechanical stirrer, thermometer, dropping funnel and return flow condenser is heated to 80 ° C for a period of 30 minutes and a solution of sodium vinylbenzenesulfonate (20.6 g, 0.1 mol) and methacrylic acid (8.6 g, 0.1 mol) in water (100 ml) is added over one period of 17 minutes. The resulting solution is heated to 80-8200 for four hours and allowed to stand overnight to cool. The the cooled solution is neutralized to pH 7.1 by adding sodium hydroxide solution (8.0 g, 0.1 mol, 50%). The solution is dialyzed in H8 hours against running deionized water, concentrated to approx 200-250 ml and then lyophilized to give 22.9 g (yield 78.6%) of the copolymer in the form of a solid white product. NMR analysis confirmed this is a polymer with a ratio of 1: 1, 2.

By essentially following the procedure of Example 12, other copolymers with varying ratios of sodium vinylbenzenesulfonate (SVBS) and methacrylic acid (MMA) with the following molecular weights: _ a. nvns (2, u7) / MAA (1) M = 850, ooo MW / Mn 2.55 n. SVBS <2) / MAA <1) M = 52n, ooo MW / M¿ 2.7 c. svns (5) / MAA (1) M = 282,000 7 svßs (H) / MAA (1) M = 250, ooo Example 15 - Copolymer of sodium vinylbenzene sulfonate and meth. acrylate.

Step A - Copolymer of vinylbenzene (2, Ä6) and methyl methacrylate (1) Vinylbenzene (10H g, 1.0 mol), methyl methacrylate (HO g, 0.1 mol), benzoyl peroxide (0.5 3, 0.002 mol) and benzene (50 ml) are added to one 500 ml flask equipped with a stirrer, water condenser and Benson (100 ml) is poured into the addition funnel.

For ten minutes, stirring at room temperature. additive funnel. The system overflowed by lucky. periodic addition of benzene to reduce the viscosity. At nitrogen The mixture is heated to 80 ”C under nitrogen for 2 hours end of the heating period, the reaction mixture is cooled and dilute with benzene (100 ml). The polymer is insulated by setting the benzene solution to vigorously stirred methanol. The solid polymer removed by filtration, washed well with methanol and dried in vacuum at 6000 to constant weight to reach 120 g (excl. 85.7%) of the product as a white solid product.

Step B - Copolymer of sodium vinylbenzene sulfonate and methyl methacrylate.

This sulfonation is carried out essentially as described in Example 12 using the following amounts of material: copolymer 10 20 25 30 - .. \ J) UG 7700670-8 20 according to step A above (} 5.6 g, 0.1 mol), 0.89 mol) 3ulfan-B (35.4 g, 0.1 H43 mol), ethylene dichloride (1025 ml) sodium hydroxide (50% solution, 35.0 g, l 400 ml). One half of the neutralized solution is dialyzed for Ä8 hours and lyophilized sym-2-chloroethyl ether (127 g, then to give 56.2 g of product as a solid product with off-white color, molexyl weight = 298 ooo, fi W / lln = 2.1.

Example 1a - Copolymer of sodium vinylbenzene sulfonate and methyl methacrylate (3.8: 1) To a solution of ammonium persulfate (H, 0 g, 0.0l? 5 mol), water (150 ml) and dimethylformamide (25 ml) in a 1 liter round bottom flask with three necks equipped with mechanical stirrer, thermo- meters, addition funnel along with reflux condenser is set at 8000 a solution of sodium vinylbenzenesulfonate (μl, 2 g, 0.2 mol) methyl methyl acrylate (5.0 g, 0.5 mol) in water (250 ml) and dimethylformamide (DMF) (75 ml) dropwise over a period of four hours. After this to a batch is added a "destroyer" of ammonium persulfate (0.5 g) dissolved in water (10 ml) and the solution is kept at 8000 for another 16 hours.

This solution is concentrated under reduced pressure to remove the water and the dimethylformamide. The resulting glassy poly- dissolve in water (500 ml), neutralize the pH 7.5 by adding batch of sodium hydroxide solution and dialyzed for H8 hours. The the dialyzed solution is concentrated to H00 ml and lyophilized to give H2.5 g of white solid product with a molecular weight of 100,700.

Example 15 - Copolymer of sodium vinylbenzenesulfonate and methacrylamide (2.2: 1) M = 350,000.

A solution of sodium vinylbenzenesulfonate (82.0 g, 0.36 mol) methacrylamide (18.9 g, 0.22 mol), ammonium persulfate (0.5 g, 0.002 mol) and water (560 ml) in a 1 liter flask is heated to 8000 with stirring under nitrogen, and kept under these conditions for 20 hours. At the end of this time period, the reaction mixture is cooled to room temperature, neutralized to pH 7.5 by adding approx 0.5 g of 25% sodium hydroxide for H8 hours, concentrated to 600 ml and lyophilized to give 83 g of white solid product with M = 350,000.

Example 16 - Copolymer of sodium vinylbenzenesulfonate and methacrylamide (2.2 = 1) M _ = 526.ogg._ The procedure of Example 15 is followed exactly except that the quantities are doubled. The neutralized solution is then dialyzed in H8 hours. Then the dialyzed is ultrafiltered (dia-filtered) the two-part solution using an XM-300 membrane in one arrangement Amicon TC-l. The conditions for ultrafiltration are as follows: Flow rate (across the membrane) 1.0-1.6 liters / min, inlet strokeà (above 10 15 2 !! 25 30 55 HO 77 ÛÛ67Û-8 21 membrane) 2.1-2.8 kp / rev, filtration speed = varying between 2 and 30 ml / min, and air pressure (on the pump) 2.1-2.5 kp / cm2. During this diafiltration (deionized water is added to retent as soon as the filtrate has been removed in order to keep the volume constant) it is necessary to periodically stop the ultrafiltration and rinse the membrane with ordinary water. At the end of the ultrafiltration, the retentate is centered to about 600 ml and lyophilized to give 92 g product 1 in the form of a white solid. Viscosity measurements indicate a molecular weight of 526,000 and a monomer distribution of 2.2: 1 by NMR analysis.

Example 17 - Copolymer of sodium vinylbenzenesulfonate and methacrylamide (2.2: 1) M = ÜÄ2.6OO The polymerization process is essentially the same as in Example 15 using the following amounts of material sensulfonate (247.2 g, 1.098 moles), water (1,000 ml), methacrylamide (56.7 g, 0.0666 mol), ammonium persulfate (1.5 g, 0.0066 mol) and sodium hydroxide (1.95 g). After the polymerization, the solvent is neutralized. diluted to a volume of about 19 liters and dialyzed by the solution is pumped through the hollow fibers of two Dow b / HFD1 dialysis vessels (in series), at a rate of 10 ml / min at the same time as deionized water is pumped through the vessel (around the hollow fibers) with a rate of 50 ml / min. The retentate (the solution, which is retained by fibers), concentrated to about 1.5 liters and lyophilized to give 273 E solid White product, M = ÅÄÖ-000.

Example 18 - Copolymer of sodium vinylbenzenesulfonate and methacrylamide (5,752l), M = 539,000¿ A solution of sodium vinylbenzene sulfate (500.4 g, 1.3215 moles), methacrylamide (76 μg, 0.88 mol) in water (deionized and deaerated, 1 343.4 g) in a round-bottomed flask with vdhm15 liters equipped with four necks and mechanical stirrers, reflux condenser, nitrogen inlet pipes and inlet pipes for liquid are heated under nitrogen with stirring to 7500. This solution is precipitated with ammonium persulfate (3.02 g, 0.01} 2) mol) in water (deionized, deaerated, 10.7 g) and stirred for 15 minutes. A third solution prepared from sodium vinylbenzenesulfonate (362.9 g, 1.586 moles) in water (deionized, deaerated, 1,286.6 g) is then pumped into the reaction mixture using a membrane variable speed pump with the following speeds: 25 ml per minute for 15 minutes, 12.5 ml per minute for 60 minutes, 6 ml per minute for 50 minutes and 3 ml per minute for 30 minutes. The reaction mixture then heated, stirred under nitrogen for a further two hours and cooled to room temperature. One third of the reaction mixture 10 15 20 25 30 55 40 . the volume to about l9 liters. 7700670-8 22 (1.5 ml) is placed in the container of an Amicon ultrafiltration device ( TCl and add sodium chloride (306 g) dissolved in water (3.0 liters), after which additional water is added to bring the total Approximately 38 liters of sodium chloride solution (0.3N) is placed in the diafilter media container and the polymer solution diafiltered using an XM-100 membrane until it heals amount of the volume of about 38 liters of sodium chloride solution passed through the order- The diafiltration is continued using deionized water as a diafilter medium until a total of about 125 liters of filtrate collected. The retentate (ie polymer solution, which has not passed through membrane) is removed from the device, concentrated and lyophilized to give 195.8 g of white solid product. Viscosity measurements indicate a molecular weight of 559,000.

Example_19 ~ Poly (sodium vinylbenzenesulfonate) Six samples of monodispersed polyvinylbenzene (Pressure Chemical Company) with molecular weights of 2,200, 20 H00, 37,000, 110,000, 200,000 and 590,000 all with fi w / Mn lower than 1.10 were sulfonated substantially as described by the procedure of Example 3 for to give poly (sodium vinylbenzene sulfonates) having molecular weights of H H00, no 800, 7u ooo, 220 ooo, 400 ooo and 780 ooo respectively, all of which exhibits a predictable value for fi wf fi ñ lower than 1.10 and also showing a molar sulfonation percentage of (the molecular weight sample H Ä00 not dialyzed) 97%, 82%, 90%, 9U%, 95% and 91%, respectively.

Example 20 - Poly (sodium vinylbenzenesulfonate) A solution of sodium vinylbenzenesulfonate (lüü g) in water (100 ml) is treated with ammonium persulphate (0.8 g) and heated for 20 h hours at 8000. According to standard treatment, poly (sodium vinylbenzene sulphonate) with a viscosity average molecular weight of 195,000.

At an oral dose of 50 mg / kg, the product gave 91% control of Shay At 100 mg / kg, it gave 36% control in histamine guinea pigs. At 100 mg / kg in steroid rat, the product gave Ul% control. When the product was given in doses of 10, 50 and 200 mg / kg in sugar solution to guinea pigs for 35 days, In particular, there was no irritation no significant pathology was noted. in the gastrointestinal tract and no dying or dead animals. Example 21 - Choline polystyrene sulfonate Sodium powder styrene sulfonate (20.6 g) is dissolved in water (15% by weight solution). To this is added 13.96 g of anhydrous choline chloride to to form the choline polystyrene sulfonate. I _ ' By essentially following the procedure described above and adding 15.96 g of choline chloride with 7.0 g of choline chloride is obtained sodium / choline polystyrene sulfonate. _ _ g ell, u- 10 15 20 STAY 55 HO 77 006 70-8 23 The following data in Table I illustrate the present products activity against ulcers. Four experimental models were selected to investigate the associations. 1 §11orous ligated_rat (16 hour experiment with Shay ~ rat) Pylnrus ligatures were formed in anus-cited female rats (200- 220 g) immediately followed by an oral dose of test compound of 50 mg / rat in a total volume of 2.0 ml of water. Control or comparison experimental animals received 2.0 ml of water. 16 hours later, the animals were killed.

Their stomachs were removed, opened along the greater curvature and that the non-glandular portion of the stomach was examined for ulcers the degree of difficulty of the formation by means of an arbitrary classification system from 0 to Ä. 2. Steroid-treated rat 0 Female rats (175-190 g) were housed individually and given food and water ad libitum. Each animal was then injected subcutaneously daily for three consecutive days with 10 mg Prednilsolone suspension in 0.2 ml of 0.5% Methocell solution, Simultaneously with Predinsolone injections, each animal received 100 mg of the test compound in 1 ml water B.I.D. orally. The rats were sacrificed on the fourth day, the gastric na was removed, opened along the larger curvature along with it the glandular portion was classified in terms of occurrence and difficulty degree of ulceration. 5. Histamine-induced ulcer in guinea pigs Male adult albino guinea pigs (400-500 g) were given a single intra- muscular injection of histamic acid phosphate with 10 mg / kg suspended in a mixture of beeswax: peanut oil (1: 9). The animals were then given oral doses of the indicated compound at 100 mg / G.P., B.I.D (f.m.-e.m.) umkm two consecutive days. The guinea pigs were killed on the third day morning. The stomachs with about 10 cm duodenum attached to it were removed.

These duodes were examined for perforations and wounds as well were classified with respect to the incidence and severity of ulceration by means of an arbitrary classification system with values from 0 to H.

U. Histamine-induced duodenal ulcer in rats Female rats (220-225 g) were injected subcutaneously with histamine-2 H01 with 350 mg / rat in a total volume of 1.0 ml. Immediately accompanying histamine injection, each rat was given an oral dose of 2 ml of a solution containing 50 mg of the test compound. 2U hours later removed the stomachs with the attached duodenum were taken and examined with respect to wound formation.

CALCULATION OF% INHIBITION l. 16 hour trial regarding ulcer activity and performed on 77 006 70-8 21: Shay rat.

The stomachs were removed and opened along the larger curvature.

The stomachs were then classified according to the following schedule.

- Total absence of hemorrhage and ulcers; - one or two small areas of hemorrhage and / or ulcers; - about 25% of the stomach with ulceration; 25 to 50% of the stomach with ulcers and perforation and / or extensive ulceration of the entire mucosa.

. Experiments regarding histamine-induced duodenal ulcer in rats. fU-IEWRJIHO The duodenum with attached sac was removed and opened.

The duodenum was then inspected for ulceration. The results reported as the number of duodenal ulcers calculated on the basis of all or none. The inhibition is given as a comparison between traded animals and animals in the control group with duodenal ulcers.

Sf Histamine-induced duodenal ulcer in guinea pigs The animals were killed and cut open and stomachs attached duodena (length about 10 cm) was carefully removed. The duodena was examined then with regard to perforations and / or obvious wounds as well as was as follows: 0 - absence of major pathology; l - l-Ä very small duodenal ulcers; 2 -;> H small areas of ulceration; 5 - severe ulceration and / or contiguous necrotic areas of the duodenum as well 4 - perforation.

Wound classification = The total number of duodes was classified as 3 or N Total number of classified duodena M. Calculations for experiments with steroid-induced acute wounds Average '' _ wound classification = Total number of wounds + incidence and severity * Number of tested animals * Difficulty - 5 0 - no clearly visible wound; l - l to H clearly visible wounds; 2 - 5 to 9 clearly visible wounds as well 3 - 10 or more clearly visible wounds.

The following criteria have been adopted for ulcer activity according to measurements in four experimental animal models. Means which do not show activity against ulcers in the Shay model nor in an avfmqdellerna for duodenal ulcers are considered inactive agents against ulcers. 1. 75-85% or higher inhibition of gastric ulcer for 16 hours the trial in Shay rats at a single dose of 50 mg / rat, orally \ .Y1 10 15 20 25 ÉÜ 7700670-8 25 2. 25-50% or higher inhibition of duodenal ulcer for 2ü hourly models with histamine-treated rat at a single dose of 50 mg / rat, orally; 3. 25-H0% or higher inhibition of duodenal ulcer in Ä8 hourly the model with histamine-treated guinea pig at a daily dose of 100 mg / animal, orally, B.I.D. for two days, without toxicity or cecal pathology and H. 25-HO% or higher inhibition of gastric ulcer in the three-day model with steroid-treated rat at a dose of 100 mg / rat, orally, B.I.D. for three consecutive days without toxicity or cekal pathology.

% Inhibition = Wound classification of control animals - wound classification of treatment the animals X 100 ' Wound classification of control animals It has been found that low molecular weight polymers are toxic when dosed to guinea pigs with histamine-induced ulcers and to rats exhibiting steroid-induced ulcers. (Polymers with lids molecular weight does not show toxicity in normal rats.) When the polymers with low molecular weight is given in doses of 1 g / kg and day to normal Guinea pigs cause these polymers usually bloody cecum or joints to death within seven days. Dogs are also particularly sensitive to low molecular weight polymers at a dose of 1 g / kg and day showing gastrointestinal intestinal bleeding, diarrhea, intestinal ulceration and liver These symptoms often persist even when High molecular weight polymers can be added complications. search completed. common guinea pigs and dogs for 50 to 90 days without significant accommodation. No secondary pathology occurs when the polymers according to the present invention is given to ulcerated animal models.

The following data in Table II show the toxicity of the compounds with low molecular weight. By toxicity is meant that the compounds cause cecal haemorrhage in some of the experimental animals (rabbits or guinea pigs) as well general ulceration of the gastrointestinal tract and bleeding in others experimental animals, which can lead to the death of the animals. 26 Cohswø fi ww xm fl xoë + 7700670-8 1 1 1 00 AN .xmv 000.000 1 mm mm mm 000,000 1 00 00 00 000.000 1 _ 00 00 00 A000.xm0 000.000 00 1 00 00 An0.xmv 000.000 00 _ 1 _ 00 00 A00.000 000.000 00 _ _ 1 00 00 A0 .wmv 000.000 1 00 00 00 A0 ~ .xm0 000.000 00 1 00 00 A0 .xmv 000.000 00 _ 00 00 00 000.000 00 __ 1 00 00 A0 .xmv 000.000 00 00 00 00 000.000 1 _ 00 00 00 A00.xmv 000.000 H0 00 00 00 000 000 1 00 00 00 _ 000.000 00 000 00 00 000 000 00 00 00 00 _ 000.00 00 00 00 00 000.00 +> 0000c0 00 +> 0000: 0 00 000.0 Q fl bmhmë .w .Hmm dßvmh .w .HWmHdGwUOSU .mßvmh ..n .Hmm MPPWLH 050520 Pßàwo fi ñ fififlfl ëdvm fl m Pßàwø fi ü flfi ü fl ëdßm fi m ... Mmäw vä flflfi ö fi Ohwum lh fl ßm. _ IHhNQHOE Ammuwzou fl ßmcwmsmn fi æn fi> Es fi numnvz fl om> m mso flfi poë pwp fl> fl ux < H QQmm 7700670- 8 27 HNDhw> M®wDO QOWWG ÜÅOH h®ß fi®> fi wmDO COWWC ÜMOH fifl D fi w> fi® WQO COHWC QNUH fi mnmw> nwmQo uowmc mxoH | mmQnw> hmmno Qowwü wxoH m: wu \ w O » m: fi ø \ w o> .A L: w @ \ w Q »+ pms fifi wm pms fi nßm pms fifi wm pms fifl wm pms fl ëwm wG fl hUQmvM fl> o fl \ c o fi \ o w \ o m \ m fifl \ m o fl \ m æ \> w \ m Umm wwo fl oumm øcsm fl mo fi ovmm _: fi> mhmE vw fl HQw> fl mo fi opmm Unsm I: fl> mhmE uw fi Hcm> fl mo fi opmm øcsm wwo fi oumm wssm | n «> wLmE vwHHCm> | : fi> mhmE um fifi Em> J: fl> mhmE uw fl HQm> I c fl> whmE uw fifi cm> c fl> wmmE HH \ w um fi øcmnmnn fi ëmumwm | c mL> mLmE uw fl Hcm> I muumhnø fl ommum | muumh | ø fl onmpm E fi xmo hßwøwxßmhmm w fi øo fi m wx \ mE wx \ mE noxom> ooæ ooæ N M mmw.o wx \ w H wx \ mE ooæ moxow> N M wm o.. o.wx \ w fl noxow> N H wmU.o wx \ m H wx \ ws cow wx \ ws som wx \ mE cow wx \ wE ooæ wx \ wa Qom wx \ wE cow mmm ooH.wmw OoH.æmm ooø.omw ^ fl N fl. Nmv ooO.omæ OoO.mHm OoO.oo: OoO.oow 000.00: Ooo.ONN Ooo.:> ooo.o: Ooo.o: Ooo .: OoO .: px fl> H> xwHoE m fl ww flfi ümhwm ux fi> HmxmaoE mn: umë mmnwäæ fl om mx flfi æu: oo ux fl> fl> xmHoE wm fi Uwä ^ hmvwQom fi: mQmw: mn | Hmn fl> E5 fi h @ mcvæHoQ> m nmæwëm fl omëmm Sao | oEoQ Gm flfi wë wmHwhmMEmwmvwu fl o fi xoB HH.Qqmm <æ mmmmø mm nmwm fl N hmwmø about mmwmu N nmmmw om fi mwmø about noxow> =. acxum> n nmmmu m fi nmwmø m fi noxoø> J Moxow> 1 noxow>: noxow> z fl w fl m fi mumxmwhwm

Claims (11)

7700670-8 28 PATENT REQUIREMENTS Therapeutic product characterized in that it consists of a homopolymer or copolymer in which at least 50% of the total monomer units are vinylbenzenesulfonate units of the formula: RI _ _ .. _.... C * _----- - -. wherein R is -H or -CH 3 and X is -H, alkyl or halo and in which any other moieties are moieties of one or more of the corresponding amides and / or esters and / or moieties of the formula: -cH (R 1) c (R 2) (R 3) - wherein R 1 and R 2 are the same or different and may be hydrogen or (C 1 -C 6) alkyl, and R 5 may be acyloxy, aroyloxy, carboxy, carbamoyl, cyano (Cl C 1-4 alkoxy, (C 1 -C 6) alkoxycarbonyl or aryl or of pharmaceutically acceptable non-toxic salts thereof, the polymer having a viscosity average molecular weight of from 100,000 to 2,000,000 and containing less than 5% by weight of polymer having a viscosity average molecular weight of 20,000 or less. Product according to claim 1, characterized in that it has at least 60% vinylbenzenesulfonate units. 3. A product according to claim Z, characterized in that it has at least 90% vinylbenzenesulfonate units. Product according to any one of the preceding claims, characterized in that the polymer has a viscosity average molecular weight of from 300,000 to 1,000,000. Product according to any one of the preceding claims, characterized in that the polymer has a molecular weight distribution of from 1.01 to 8. A product according to any one of the preceding claims, characterized in that R is -H, X is -H and R 1, if present, is -H. Product according to any one of the preceding claims, characterized in that R 1 is -H and R 3 is acetoxy, carboxy, carbamoyl (C 1 -C 6) alkoxy, (C 1 -C 6 alkoxycarbonyl or phenyl). Product according to any one of the preceding claims, characterized in that the polymer contains less than 5% of polymer with a viscosity average molecular weight of 50,000 or less. Product according to any one of the preceding claims, characterized in that the polymer contains units of one or more of: vinylbenzene, alkyl acrylate, alkyl methacrylate, vinyl nitrile, acrylic acid, methacrylic acid, ethylenically unsaturated aldehyde, ethylenically unsaturated imide, ethylenically unsaturated olefin, vinyl ester and vinylamide. 10. A product according to claim 9, characterized in that it contains units of one or more of: methyl methacrylate, maleic anhydride, methacrylamide and methacrylic acid. ll. Product according to any one of the preceding claims, characterized in that it consists of vinylbenzene units, of which more than 90% are sodium vinylbenzene sulfonate units, the polymer having a viscosity average molecular weight of from 400,000 to S00,000 and a molecular weight distribution of 3 or less. REQUIRED PUBLICATIONS: US 3,893,890 (195-104), 3,961,045 (424-78)